Among di(pyrimidine nucleoside 5′-)polyphosphates represented by the following formula (I):
(wherein, each of R1 and R2, which may be identical to or different from each other, represents a hydrogen atom or a hydroxyl group; each of B1 and B2, which may be identical to or different from each other, represents a pyrimidine base; and n is an integer from 1 to 4), for example, P1,P4-di(uridine 5′-)tetraphosphate (Up4U) or a salt thereof is a compound which exhibits an expectoration-inducing effect and thus is envisaged to be developed as an expectorant or a therapeutic drug for pneumonia, and P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate (dCp4U) or a salt thereof is a compound which is a selective agonist for P2Y2 and/or P2Y4 purine receptor and thus is envisaged to be developed as a therapeutic drug for, for example, chronic bronchitis or sinusitis.
In a method for synthesizing such a di(pyrimidine nucleoside 5′-)polyphosphate, for example, Up4U is produced from uridine 5′-monophosphate (UMP) serving as a starting material by use of an activator (e.g., diphenyl phosphorochloridate (DPC)) and a phosphorylating agent (e.g., pyrophosphate (PPi)). However, such a method has failed to be put into practice, since the method produces a target compound at a very low synthesis yield (i.e., a little less than 10% or thereabouts) (Patent Document 1).
For improvement of such a method, attempts have been made to develop a method for synthesizing a di(pyrimidine nucleoside 5′-)polyphosphate via a nucleoside 5′-cyclic triphosphate. Specifically, there have been reported a method for preparing Up4U by reacting uridine 5′-cyclic triphosphate with UMP (Non-Patent Document 1), and a method for preparing P1,P4-di(adenosine 5′-)tetraphosphate by reacting adenosine 5′-cyclic triphosphate with adenosine 5′-monophosphate (Non-Patent Document 2).    Patent Document 1: WO99/5155    Non-Patent Document 1: Bioorganic & Medicinal Chemistry Letters, 11 (2001), 157-160    Non-Patent Document 2: Organic Letters, Vol. 8, No. 10, 2075-2077 (2006)